Glucose 6-phosphate dehydrogenase deficiency increases redox stress and moderately accelerates the development of heart failure.
Glucose 6-phosphate dehydrogenase deficiency increases redox stress and moderately accelerates the development of heart failure.
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DOI：
10.1161/circheartfailure.112.969576
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发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Stanley WC
中科院分区：
文献类型：
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作者：
Hecker PA;Lionetti V;Ribeiro RF Jr;Rastogi S;Brown BH;O'Connell KA;Cox JW;Shekar KC;Gamble DM;Sabbah HN;Leopold JA;Gupte SA;Recchia FA;Stanley WC
6-磷酸葡萄糖脱氢酶（G6PD）缺乏症是世界上最常见的酶缺乏症。在衰竭的心脏中，G6PD 上调并产生 NADPH，谷胱甘肽途径使用 NADPH 来去除活性氧 (ROS)，同时也作为 ROS 生成酶的底物。因此，G6PD 缺乏可能通过减少 NADPH 和 ROS 的产生来预防心力衰竭。这一假设在人类 G6PD 缺乏症小鼠模型（G6PDX 小鼠，约 40% 正常活性）中进行了评估。 3 个月随访后的心肌梗塞导致 WT 和 G6PDX 小鼠的左室扩张和功能障碍，但 G6PDX 小鼠的舒张末期容积显着增加且壁变薄。同样，横向主动脉缩窄 (TAC) 引起的压力超负荷 6 周导致 G6PDX 小鼠比 WT 小鼠更大的左室扩张。我们通过喂食高果糖饮食来增加 G6PD 和 ROS 产生的流量，进一步对 TAC 小鼠施加压力，并再次观察到 G6PDX 比 WT 小鼠有更差的左室重塑和更低的射血分数。 G6PDX 小鼠中，梗塞后脂质过氧化产物的组织含量增加，而 TAC 则降低乌头酸酶活性，表明 G6PD 缺乏会增加心肌氧化应激和随后的损伤。与我们的假设相反，G6PD 缺乏会增加梗死或压力超负荷时的氧化还原应激。然而，我们发现左心室重构仅适度加速，这表明，在 G6PD 缺乏且并发高血压或心肌梗塞的个体中，发生心力衰竭的风险较高，但受到代偿机制的限制。
Glucose 6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency in the world. In failing hearts, G6PD is upregulated and generates NADPH that is used by the glutathione pathway to remove reactive oxygen species (ROS), but also as a substrate by ROS-generating enzymes. Therefore, G6PD deficiency might prevent heart failure by decreasing NADPH and ROS production. This hypothesis was evaluated in a mouse model of human G6PD deficiency (G6PDX mice, ~40% normal activity). Myocardial infarction with 3 months followup resulted in LV dilation and dysfunction in both WT and G6PDX mice, but significantly greater end diastolic volume and wall thinning in G6PDX mice. Similarly, pressure overload induced by transverse aortic constriction (TAC) for 6 weeks caused greater LV dilation in G6PDX mice than WT. We further stressed TAC mice by feeding a high fructose diet to increase flux through G6PD and ROS production, and again observed worse LV remodeling and a lower ejection fraction in G6PDX than WT mice. Tissue content of lipid peroxidation products was increased in G6PDX mice in response to infarction and aconitase activity was decreased with TAC, suggesting that G6PD deficiency increases myocardial oxidative stress and subsequent damage. Contrary to our hypothesis, G6PD deficiency increased redox stress in response to infarction or pressure overload. However, we found only a modest acceleration of LV remodeling, suggesting that, in individuals with G6PD deficiency and concurrent hypertension or myocardial infarction, the risk for developing heart failure is higher, but limited by compensatory mechanisms.